NT5C2 inhibitors for the treatment of chemotherapy-resistant acute lymphoblastic leukemia

Inventors

Dieck, Chelsea • Ferrando, Adolfo • Zask, Arie • Stockwell, Brent

Assignees

Columbia University in the City of New York

Abstract

Various embodiments relate to compounds, having structures according to Structure A or Structure B, as specified herein. The compounds according to various embodiments may inhibit NT5C2 nucleotidase. The compounds according to various embodiments may synergistically decrease cell viability of NT5C2 R367Q mutant lymphoblasts when used in combination with 6-mercaptopurine (6-MP) to treat a cancer. The cancer may be, but is not limited to, acute lymphoblastic leukemia. Various embodiments relate to a compositions that may include one or more compounds according to any embodiment described herein or a pharmaceutically acceptable salt or derivative thereof and a pharmaceutically acceptable carrier. Various embodiments relate to methods of treating cancer. The method may comprise administering a therapeutically effective amount of one or more compounds according to any embodiment described herein or a pharmaceutically acceptable salt or derivative thereof.

Core Innovation

Various embodiments relate to compounds, having structures according to Structure A or Structure B, that may inhibit NT5C2 nucleotidase and that may synergistically decrease cell viability of NT5C2 R367Q mutant lymphoblasts when used in combination with 6-mercaptopurine (6-MP) to treat a cancer, which may be, but is not limited to, acute lymphoblastic leukemia. Various embodiments relate to compositions comprising one or more compounds described herein or a pharmaceutically acceptable salt or derivative thereof and a pharmaceutically acceptable carrier, and to methods of treating cancer comprising administering a therapeutically effective amount of one or more described compounds or pharmaceutically acceptable salts or derivatives thereof.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with a high rate of secondary chemotherapy resistance at relapse, and gain of function mutations in NT5C2 are detected in a substantial fraction of relapse T-ALL cases; therefore, NT5C2 inhibitors can potentially treat T-ALL and relapsed T-ALL by enhancing the efficacy of existing chemotherapy treatments.

Various embodiments describe the synthesis and characterization of NT5C2 inhibitors including HTP47 and HTP48 and report that HTP47 and HTP48 demonstrated NT5C2 inhibitory activity and act synergistically with 6-mercaptopurine (6-MP) in a dose-dependent manner to decrease cell viability of NT5C2 R367Q mutant mouse lymphoblasts; [procedural detail omitted for safety].

Claims Coverage

The independent claims recite two methods of treating cancer and disclose seven main inventive features related to administration of specified compounds, their NT5C2 inhibition activity, synergistic use with 6-MP, disease indication, co-administration with adjunct agents, identity of adjunct agents, and formulation with a pharmaceutically acceptable carrier.

The independent claims cover methods of treating cancer by administering specified compounds that inhibit NT5C2, including embodiments where the compounds act synergistically with 6-MP against NT5C2 R367Q mutant lymphoblasts, are used to treat acute lymphoblastic leukemia, may be co-administered with adjunct agents (including purine analogs), and may be formulated with pharmaceutically acceptable carriers.

Stated Advantages

Documented Applications